Cancer and the Cavalier King Charles Spaniel

While many cavalier King Charles spaniels develop cancer, and it is the breed’s second leading cause of death, few forms of cancer are more common in the CKCS than in other purebred breeds of dogs.  The ones that are include anal sac gland carcinoma, squamous cell carcinoma, and diffuse large B-cell lymphoma (DLBCL), and are discussed below.

Here, we provide information about the forms of cancer most common to dogs, and to cavaliers in particular, as well as the causes of those cancers, if known, and current treatments. There are several other websites with far more detailed information on the topics of canine cancer. See Related Links below.

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What It Is

Cancer is a mutation of genes which normally control the growth of cells in the dog’s body. Cancer appears as the uncontrolled growth and division of abnormal cells and which are able to invade other tissues.

There are several types of cancer, including carcinoma (which begins in the skin or in tissues that line or cover internal organs), sarcoma (which begins in connective or supportive tissue, such as bone, muscle, cartilage, and blood vessels), leukemia (which begins in the bone marrow or other blood cell producing tissues and causes abnormal blood cells to enter the blood), lymphoma and myeloma (which begin in the cells of the immune system), mastocytoma (which begins on the skin), and central nervous system cancers (which begin in the brain and spinal cord), such as meningioma and neuroblastoma. There are other forms in addition to these.

A cancer often is named for the organ in which it first appears, but it can spread to other parts of the body through the blood system and lymph system. It starts as a mutation of a cell, likely due to radiation or chemical damage or a change in the cell’s genetic material. A mutation can affect the normal growth of that cell and its division into new cells, which also are mutated.

The mutated cells may form a mass, called a tumor (a neoplasm), which could be either malignant or benign. A benign tumor is not cancerous and often can be removed and not grow back or spread to other organs. A malignant tumor is one which continues to grow, often rapidly, invading the function of the organ, and which may spread to other parts of the body (metastasis). These cells also are regressive, non-specialized, and display a loss of structural and functional differentiation of normal cells.

Not all cancerous cells form tumors. Leukemia, for example, spreads through the blood system without creating a tumor.

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Forms of Dog Cancers

Some forms of cancer are more common among dogs than others. They include:

Osteosarcoma: This bone cancer may be discovered as a painful swelling within a bone, and is visible on an x-ray. However, it may already have grown so rapidly that it has spread to other organs, such as the lungs, by the time the swelling is first noticed. Osteosarcoma cells lack the strength of normal bone cells, and as they grow and replace the normal bone structure, they weaken the bone to the point that it will collapse.

Lymphoma: Canine malignant lymphoma is a progressive, fatal disease caused by the malignant clonal expansion of lymphoid cells. Although lymphoid cell neoplastic transformation is not restricted to specific anatomic compartments, lymphoma most commonly arises from organized lymphoid tissues iCancerous Lymphoblastsncluding the bone marrow, thymus, lymph nodes, and spleen. In addition to these primary and secondary lymphoid organs, common extranodal sites include the skin, eye, CNS, testis, and bone. Lymphoma is reported to be the most common hematopoietic neoplasm in dogs, with an incidence reported to approach 0.1% in susceptible, older dogs. Despite the prevalence of malignant lymphoma, its etiology remains poorly characterized. Hypothesized etiologies include retroviral infection, environmental contamination with phenoxyacetic acid herbicides, magnetic field exposure, chromosomal abnormalities, and immune dysfunction. (The Merck Veterinary Manual). A cavalier was included in a 2003 study of 25 dogs diagnosed with canine multicentric lymphoma, which also had chromosome imbalances. In a 2012 study, researchers reported that diffuse large B-cell lymphoma (DLBCL) "is prevalent in Cavalier King Charles Spaniel". A cavalier was included in a 2012 UK study of eleven dogs with rectal lymphoma.

In a January 2014 article, an 8-year old neutered female cavalier King Charles spaniel was found to have T-cell lymphoma which had spread through the nervous system to numerous organs. The researchers noted that heretofore, involvement of peripheral nerves in spreading neoplastic lymphocytes is very rare in any veterinary species.

Lymphosarcoma.

White blood cell.

Mast cell tumor: histiocytic mastocytoma, mast cell sarcoma, mastocystosis. Mast cell tumors (right) account for about 10% of all skin tumors in dogs. Tumors on the perineum, digits, or prepuce in dogs appear to be more aggressive than those on the trunk. In an April 2013 report, a UK clinic found that cavaliers are "underrepresented" in terms of pre-disposition to developing mast cell tumors.

Mammary tumor: tubular adenocarcinoma, papillary adenocarcinoma, papillary cystic adenocarcinoma, solid carcinoma, anaplastic carcinoma, fibrosarcoma. This is found largely in females. It appears as a lump beneath the skin on the breast. In a 2011 report, the cavalier breed was identified as being at low-risk for mammary tumors. However, in a 2012 Swedish study, the researchers found that 15% of female cavalier King Charles spaniels developed mammary tumors by the age of ten years.

Adrenal cortical tumor: This is a tumor of the cortisol-producing cells of the adrenal gland. It is known to cause a form of Cushing's Disease.

Pituitary tumor: This tumor produces excessive amounts of ACTH -- adrenocorticotrophic hormone, the hormone which causes the adrenal glands to produce cortisol). It also is known to cause a form of Cushing's Disease.

Anal sac gland carcinoma: A couple of studies of this form of cancer in cavaliers has been reported. One 2005 report and another in 2009. In the 2009 report, the author states that "English Cocker spaniels (and to a lesser extent Springer and Cavalier King Charles spaniels) are at higher risk of developing anal sac tumours than other dogs. This conclusion is based upon the analysis of large numbers of cases of anal sac tumours using data from veterinary pathology laboratories and breed registration data from The British Kennel Club." See also this January 2013 study.

SSquamous Cell Carcinomaquamous cell carcinoma: In both a 2008 study and a 2011 study of this cancer (right) in the cornea, which included three CKCSs, the authors found that it was related to chronic dry eye, which is a very common disorder in this breed. This form of carcinoma also is known to develop within the mouths and throats of cavaliers.  Also, see this 2011 report of a study of 44 dogs with tonsillar squarmous cell carcinoma, including four cavaliers.

Conjunctival hemangioma and hemangiosarcoma: In a 2006 study in which cavaliers were included, the authors concluded that ultraviolet light played a significant role in the cancer's development.

Meningioma: In a 2010 report, a cavalier was found to have a meningioma in a post-mortem examination. The authors noted that, "isolated unilateral facial myokymia preceding diagnosis of a meningioma affecting facial nerve function within the caudal cranial fossa and the remarkably long duration of neurological signs (75 months) attributable to the neoplasm."

Sebaceous gland adenocarcinoma.

Acute lymphocytic leukemia: In a February 2012 report from North Carolina State University's veterinary school, a CKCS suffering from this cancer was treated with bone marrow containing peripheral blood progenitor cells which were extracted from a litter mate and transplanted into the patient.

Melanoma: canine melanoma, oral melanoma. Typically, canine melanoma is found in the mouth (oral melanoma), on toes, behind the eyes, or on the skin, but it may develop anywhere.

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Causes

Squamous tumor in mouth of CKCSThe primary causes associated with the development and growth of cancerous cells are wide-ranging. They include:

Exposure to certain forms and quantities of radiation.

Exposure to certain chemicals which can damage cells’ genetic structure (mutagens and carcinogens in the environment and diet). in a 2012 study, lawn-care pesticides have been among those chemicals identified as increasing the risk of malignant lymphoma in dogs.

Certain hormones, such as oestrogen and testosterone.

Certain viruses.

Genetic pre-disposition.

Excessive stress and depression (yes, dogs can suffer both).

A confused immune system.

Neutering: Hemangiosarcoma (HSA) is a cancer that is affected by neutering in females. cardiac HSA for spayed females was greater than 4 times that of intact females. A study on splenic HSA found the spayed females had more than 2 times the risk of developing this tumor as intact females. Intact females had a significantly lower risk of developing LSA (lymphoma) than neutered females or neutered males or intact males. A study on cutaneous mast cell tumors (MCT) in several dog breeds examined risk factors such as breed, size, and neuter status. The results showed a significant increase in frequency of MCT in neutered females; four times greater than that of intact females. See this February 2013 report.

In a In a February 2014 report about 2,505 Vizslas, researchers found that: (a) Mast cell cancer: 3.5 times higher incidence in neutered male and female dogs, independent of age at the time of neutering. (b) Hemangiosarcoma: 9.0 times higher incidence in neutered females compared to nonneutered females, independent of age at the time spaying was performed. No difference in incidence of this disease was found for neutered versus nonneutered males. (c) Lymphoma (lymphosarcoma): 4.3 times higher incidence in neutered male and female dogs, independent of age at the time of neutering. (d) Other types of cancer: 5.0 times higher incidence in neutered male and female dogs. The younger a dog was at the time of neutering the younger the age of the dog at the time the cancer was diagnosed. (e) All cancers combined: 6.5 times higher incidence of cancer in neutered females compared to nonneutered females; 3.6 times higher incidence of cancer in neutered males compared to nonneutered males.

Not spaying and delayed spaying? It long had been reported that a female's risk of developing mammary cancer is greatly reduced by spaying, and the earlier the better. However, in a June 2012 review of all of these prior studies, the authors found that: "Due to the limited evidence available and the risk of bias in the published results, the evidence that neutering reduces the risk of mammary neoplasia, and the evidence that age at neutering has an effect, are judged to be weak and are not a sound basis for firm recommendations."

Some medications. In both a 2008 study and a 2011 study, the researchers concluded that dogs (including cavaliers) treated with cyclosporine for dry eye are at risk to develop axial corneal squamous cell carcinoma.

Possibly a consequence of surgery. In a 2010 report, a cavalier developed multiple inverted papilloma, which were benign tumors, following an ovariohysterectomy.

To some extent, dogs living longer lives are at greater risk of cancer eventually developing.

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Symptoms

See VetDepot's "Symptoms of Cancer in Dogs and Cats" and Colorado State University's Animal Cancer Center's "Top 10 Warning Signs of Cancer in Pet Animals".

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Diagnosis

See VetDepot's "Diagnosing Cancer in Dogs and Cats".

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Treatment

The form of treatment depends upon the form of the cancer. The options include:

IV Drip Chemotherapy, which consists of doses of toxic active ingredients that are intended to destroy rapidly dividing cancer cells but to spare the normal cells. Recent research has produced compounds of procaspase-3 activating compound 1 (PAC-1), which has been effective in killing lymphoma cells in dogs. See the reports discussed below herein: September 2010, October 2011, and January 2012.

Bone marrow transplants, using donor bone marrow containing peripheral blood progenitor cells, for treating dogs with lymphoma or lymphocytic leukemia.

Radiation therapy, which is a beam of radiation aimed at the cancerous tumor.

Surgery to remove tumors.

Vaccines, including Oncept by Merial, is immunotherapy reportedly for dogs with stage II or III oral melanoma, to help achieve local disease control.

Electrocautery and cryosurgery.

I-Therm Hyperthermia, such as I-Therm treatments.

Cryotherapy.

Immunotherapy, including immune enhancement formula compounds, such as PetLife, which includes chrysin, Coriolus Versicolor, diindolymethane (DIM), Resveratrol, turmeric extract (curcumin), Quercetin, green tea extract, and l-selenium methionine.

Prescriptive medications, such as: Palladia (toceranib phosphate), a tyrosine kinase inhibitor, used to treat mast cell tumors; and Oncept, a canine oral melanoma therapeutic vaccine, is a tyrosinase inhibitor.

PetLife Immune Enhancement Formula Holistic care can include some of the above modalities, such as hyperthermia and immunotherapy, as well as types of palliative care. An overview of holistic treatments of cancer is A Holistic Approach for the Treatment of Cancer. by Joseph Demers, DVM.

Palliative care, to manage the cancer and its symptoms, and improve quality of life, when cure is not an option.

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Research News

February 2014: Pet food specialist links dry kibble to increase in pets' cancer. In a December 2013 Kibble Bowlarticle in Food Safety News, Barbara Royal, D.V.M., of The Royal Treatment Veterinary Center in Chicago, is concerned about how dry kibble is processed:

“The extrusion process (a high heat processing), creates two potent carcinogens, a heterocyclic amine and an acrylamide, which will be in every extruded kibble food, but certainly not be on the label. It is a byproduct of  the extrusion process, and because it is not an ingredient that is added, it need not be put on the label,” she explains.
“So owners are unaware that, with every bite, they are feeding a potent carcinogen. I believe that this is one reason we are seeing such an increase in cancers in our pets.”

January 2014: Study of 2,500+ Vizslas find neutering results in "significantly increased odds" of developing certain cancers. In a February 2014 report in JAVMA of 2,505 Vizslas, researchers found that neutered males "had significantly increased odds of developing mast cell cancer, lymphoma, all other cancers, all cancers combined, and fear of storms, compared with the odds for sexually intact dogs." Neutered females "had significantly increased odds of developing hemangiosarcoma". Further, they found that the younger the age at neutering, "the earlier the mean age at diagnosis of mast cell cancer, cancers other than mast cell, hemangiosarcoma, lymphoma, all cancers combined, a behavioral disorder, or fear of storms."

January 2014: Cavalier dies of fast-spreading T-cell lymphoma through the nervous system. A team of Japanese veterinarians report in a January 2014 article about an 8-year old neutered female cavalier King Charles spaniel with T-cell lymphoma which had spread through the nervous system to numerous organs. They noted that heretofore, involvement of peripheral nerves in spreading neoplastic lymphocytes is very rare in any veterinary species.

April 2013: UK study finds CKCSs not pre-disposed to mast cell tumors. In an April 2013 report, a UK clinic has found that cavaliers are "underrepresented" in terms of pre-disposition to developing mast cell tumors. This study appears to contradict a 2012 Swedish study which reached an opposite finding.

February 2013: Neutering may affect dog's risk for developing certain cancers. A University of California at Davis study of golden retrievers has found that early neutering was associated with an increase in the occurrence of lymphosarcoma in males. Late neutering was associated with the subsequent occurrence of mast cell tumors and hemangiosarcoma in females.

January 2013: VetDC announces research for canine lymphoma drug. Veterinary Emerging Technologies Development Corporation (VetDC) has announced that is is funding the development of an anti-proliferative agent that preferentially targets lymphoid cells and works by inhibiting cellular DNA synthesis, leading to the induction of apoptosis, or programmed cell death. The agent is tagged VDC-1101. The drug was originally tested on dogs but was developed for human use. VetDC aims to make it available for dogs within two years.

In a prior study, VDC-1101 reportedly demonstrated substantial antitumor activity in dogs with both treatment-naïve and refractory lymphoma when administered on an every three-week schedule. Dr. David Vail, professor of oncology at the University of Wisconsin-Madison School of Veterinary Medicine, said “We are very encouraged by the results of this analysis, given the high unmet need for novel, effective veterinary anti-cancer agents, particularly in the refractory setting. These results indicate that VDC-1101 may be a powerful and convenient new therapeutic option for treating lymphoma in companion animals.” See VetDC's website for more information.

December 2012: Swedish study finds high percentage of mammary tumors in cavaliers. In a retrospective study (from 1995 through 2006) of Swedish dogs, the researchers found that 15% of female cavalier King Charles spaniels developed mammary tumors by the age of ten years.

November 2012: Penn Vet School extends its mushroom research. Penn Vet School has announced that it is enrolling patients into a new clinical trial for dogs with splenic hemangiosarcoma. Its press release states, "This trial will be evaluating the effects of a traditional chinese medicine supplement with anti-cancer properties." Obviously, this would be the Coriolus versicolor mushroom discussed below. Its announcement goes on: "A previous trial using the supplement significantly increased survival time in dogs with this type of cancer." Contact the researchers for more information: vcic@vet.upenn.edu or 215-573-0302.

Coriolus versicolor mushroomNovember 2012: Mushroom compound extends life of dogs with cancer, study finds. In a 2012 study, Penn Vet School researchers reported that dogs with hemangiosarcoma that were given a compound derived from the Coriolus versicolor mushroom (Yun Zhi [I’m-Yunity]) (right) had the longest survival times ever reported for dogs with the disease.

In a later interview, researcher Cimino Brown said:

“We were shocked. Prior to this, the longest reported median survival time of dogs with hemangiosarcoma of the spleen that underwent no further treatment was 86 days. We had dogs that lived beyond a year with nothing other than this mushroom as treatment”.

Shocked? In fact, Coriolus versicolor has been used as a medicinal mushroom in traditional Chinese medicine for over 2,000 years. The substance in the mushroom believed to be beneficial in fighting cancer is polysaccharopeptide, (PSP). The immune enhancement formula compound PetLife contains Coriolus versicolor.

August 2012: Lymphoma is reported to be prevalent in CKCS. Italian researchers report in Hematological Oncology that "Diffuse large B-cell lymphoma (DLBCL) is prevalent in Cavalier King Charles Spaniel".

June 2012: Early spaying does not mean reduced risk for mammary cancer. In a June 2012 review of studies of neutering and mammary cancer in dogs, the authors found that:

"Due to the limited evidence available and the risk of bias in the published results, the evidence that neutering reduces the risk of mammary neoplasia, and the evidence that age at neutering has an effect, are judged to be weak and are not a sound basis for firm recommendations."

Zeke & ChipFebruary 2012: N. C. State University performs bone marrow transplant on a CKCS. Dr. Steven Suter, assistant professor of oncology at North Carolina State University, treated a cavalier King Charles spaniel named Zeke (pictured at left), suffering from acute lymphocytic leukemia (ALL), by transplanting bone marrow from his littermate Chip (pictured at right).

"We do require a donor, since we can not harvest progenitor cells from the patient. Leukemia patients have too many cancer cells floating around in their blood, so the machine would harvest them also. So, we find a matched donor who does not have cancer obviously, and harvest the cells from them,” Dr. Suter said. “We don't use this procedure regularly to treat dogs with leukemia ... we've treated two dogs with leukemia. We use it mainly to treat dogs with lymphoma, which is a very different disease."

He hopes that cases like Chip and Zeke will lead to a donor database for dogs, similar to the sort that people use. The typical cost of such a procedure is reportedly $15,000.00. Read more here.

January 2012: Some lawn care chemicals may increase the risk of canine malignant lymphoma. A 2012 report of a six-year study of 263 dogs at the Foster Hospital for Small Animals at Tufts University’s Cummings School of Veterinary Medicine, has shown that certain lawn pesticides (which were not identified in the study) may increase the risk of malignant lymphoma in dogs.

January 2012: Researchers find new anti-cancer PAC-1 compounds multi-fold more potent than PAC-1 researchers Drs. Hergenrother and Fan and cancer patient BlazePAC-1. PAC-1 researchers Danny C. Hsu, Howard S. Roth, Diana C. West, Rachel C. Botham, Chris J. Novotny, Steven C. Schmid, and Paul J. Hergenrother (at left in photo) report in a January 2012 study that PAC-1 compounds were "two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3." See also these October 2011 and September 2010 entries below.

Update: In an August 2013 newspaper article, Dr. Hergenrother stated that PAC-1 targets a cellular enzyme called procaspase-3 found at elevated levels in many forms of cancers, including those of the breast, colon, liver, lung, skin, blood and brain. "It gives cancer cells a signal to commit suicide," he said, but PAC-1 also spares the normal cells and can penetrate brain tumors.

December 2011: Good News: study finds CKCSs at low risk for mammary tumors. In a study by Norwegian canine geneticists of the identification of genetic variation in 11 candidate genes of canine mammary tumour, the the cavalier King Charles spaniel breed was identified as being at low-risk for mammary tumors.

October 2011: Univ. of Illinois researchers find PAC-1 compound signals canine lymphoma cancer cells to self-destruct. In an October 2011 report, University of Illinois researchers, led by chemistry professor Paul Hergenrother, have found that procaspase-3 activating compound 1 (PAC-1) acts as an anti-cancer agent which signals lymphoma cancer cells in canines to self-destruct. See also this September 2010 entry below.

In conclusion, PAC-1 is a small molecule that preferentially activates procaspase-3 to caspase-3, and induces apoptotic death in canine and human B-cell lymphoma lines. PAC-1 can be safely administered to research dogs and be consistently maintained at concentrations for prolonged periods of time which are predicted to exert anticancer effects.

February 2011: TGen needs spaniel DNA samples. The Translational Genomics Research Institute (TGen) seeks DNA samples from healthy spaniels to establish a genetic backdrop of healthy bloodlines against which genetic signatures of disease susceptibility can be deciphered and to perform periodic population surveys. Details are at http://www.tgen.org/research/canine-spaniel-frm.cfm

September 2010: PAC-1 anti-cancer compound found safe and effective in dogs with lymphoma. In a September 2010 study of a PAC-1 (procaspase-3 activating compound 1) derivative called S-PAC-1 (sulfonamide-PAC-1), the S-PAC-1 (administered as a 24- or 72-hour continuous IV infusion) in 6 pet dogs with spontaneously-occurring lymphoma revealed this compound to be safe in all 6 dogs and effective at reducing or stabilizing tumor growth in 4 out of 6 of them.

January 2009: Researchers seek DNA samples of cavaliers for anal sac gland carcinoma study.  University of Cambridge veterinary oncologists are soliciting blood samples of cavaliers (and other spaniel breeds) either affected with anal sac gland carinoma or non-affected.

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Related Links

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Veterinary Resources

Chromosome aberrations in canine multicentric lymphomas detected with comparative genomic hybridisation and a panel of single locus probes. R Thomas, K C Smith, E A Ostrander, F Galibert, and M Breen. Brit J Cancer; Oct. 2003;89(8):1530–1537. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394339/?tool=pmcentrez  Quote: "Malignant lymphoma (lymphosarcoma) represents one of the most frequently encountered canine neoplasms, most commonly affecting middle-aged to older dogs of a wide range of breeds. The disease originates from the malignant transformation of developing lymphocytes, and in the absence of chemotherapy, survival beyond one month after diagnosis is uncommon. Although generally considered a chemoresponsive form of malignancy in the dog, .. the disease is highly heterogeneous at both the clinical and histological level. A proportion of cases demonstrate more favourable response to therapy, and longer overall survival time, than others receiving the same initial diagnosis. ... Since humans and dogs demonstrate extensive genome homology, it is likely that canine lymphoma will also be associated with recurrent chromosome aberrations. However, few reports exist describing chromosome abnormalities detected in canine lymphoma and at present insufficient data are available from which to draw significant conclusions on their findings. ... The development of comparative genomic hybridisation (CGH) as a technique for indirect analysis of chromosomal copy number changes in human tumour cells now provides a means by which imbalanced genomic aberrations can be identified accurately and efficiently without the need to generate tumour chromosome preparations. The application of CGH to the dog, the advent of novel molecular cytogenetic resources for this species, the development of comparative cytogenetic maps and the generation of an integrated canine genome map now provide a means by which to overcome prior practical difficulties and embark on more comprehensive studies of tumour karyotypes in this species. ... We have used CGH analysis to identify chromosome imbalances in 25 cases [including one cavalier King Charles spaniel] of canine multicentric lymphoma. The resulting range and distribution of aberrations observed indicates that, as with the human counterpart of this disease, the cytogenetic profiling of canine lymphoma as a potential aid to diagnosis and clinical management warrants more detailed investigation."

Anal sac tumours of the dog and their response to cytoreductive surgery and chemotherapy. S.G. Emms. Austr Vet J; June 2005;83(6):340-343. Quote: "A retrospective study of anal sac tumours without pulmonary metastases, from the author's clinical records for the period July 1989 to July 2002, was conducted to establish the response to treatment with surgery and melphalan chemotherapy. Of 21 dogs [including cavalier King Charles spaniels] with tumours of the anal sacs 19 had apocrine gland adenocarcinomas of anal sac origin, one had a benign papillary cystadenoma and another had a malignant melanoma. Two of the 19 dogs had bilateral anal sac adenocarcinomas. Ten of the 19 dogs with apocrine gland adenocarcinomas of anal sac origin had sublumbar lymphadenopathy. Five dogs were excluded by their owners from recommended treatment. Fourteen dogs with apocrine gland adenocarcinomas of anal sac origin were treated by surgical cytoreduction and chemotherapy with melphalan. Seven of the 14 dogs had regional lymph node metastases. Cytoreduction was by local excision of the anal sac in all 14 dogs and concurrent removal of the sublumbar retroperitoneal lymph nodes in the seven dogs with regional lymph node metastases. The median survival time of dogs with sublumbar nodal metastasis was 20 months and for dogs with tumour localised to the anal sac the median survival time was 29.3 months. There was no difference in median survival of those dogs with sublumbar metastases compared to those without. This study suggests there is a role for melphalan in the treatment of dogs with anal sac adenocarcinoma when combined with cytoreductive surgery, with treatment survival times and the local recurrence rate of the primary tumour comparing favourably with previously published treatment regimes."

Primary Renal Neoplasia of Dogs. Jeffrey N. Bryan, Carolyn J. Henry, Susan E. Turnquist, Jeff W. Tyler, Julius M. Liptak, Scott A. Rizzo, Gabriella Sfiligoi, Steven J. Steinberg, Annette N. Smith, and Tarraca Jackson. J Vet Intern Med 2006;20:1155–1160. Quote: "Background: Primary renal tumors are diagnosed uncommonly in dogs. Hypothesis: Signs and survival will differ among different categories of primary renal tumors. Animals: Data were collected from the medical records of 82 dogs [including a cavalier King Charles spaniel] with primary renal tumors diagnosed by examination of tissue obtained by ultrasound-guided biopsy, needle aspiration, surgery, or at postmortem examination. Results: Forty-nine dogs had carcinomas, 28 had sarcomas, and 5 had nephroblastomas. The dogs were geriatric (mean 8.1 years; range: 1–17) with a weight of 24.9 kg (range: 4.5–80). Tumors occurred with equal frequency in each kidney with 4% occurring bilaterally. Initial signs included one or more of hematuria, inappetance, lethargy, weight loss, or a palpable abdominal mass. Pain was reported more frequently in dogs with sarcomas (5/28). The most common hematologic abnormalities were neutrophilia (22/63), anemia (21/64), and thrombocytopenia (6/68). Polycythemia was present in 3 dogs and resolved with treatment. Hematuria (28/49), pyuria (26/49), proteinuria (24/50), and isosthenuria (20/56) were the most frequently observed abnormalities on urinalysis. Pulmonary metastases were noted on thoracic radiographs in 16% of dogs at diagnosis. Seventy-seven percent of dogs had metastatic disease at the time of death. Median survival for dogs with carcinomas was 16 months (range 0–59 months), for dogs with sarcomas 9 months (range 0–70 months), and for dogs with nephroblastomas 6 months (range 0–6 months). Conclusions and Clinical Importance: Primary renal tumors in dogs are generally highly malignant with surgery being the "only treatment that improves survival."

Canine conjunctival hemangioma and hemangiosarcoma: a retrospective evaluation of 108 cases (1989–2004). Chris G. Pirie, Amy M. Knollinger, Chet B. Thomas, Richard R. Dubielzig. Vet Ophth; July 2006;9(4):215-226. Quote: "Canine conjunctival tumors of vascular endothelial origin are common, although under-reported. The purpose of this study was to evaluate the epidemiology of and potential risk factors for these tumors. This study evaluated 108 cases [including cavalier King Charles spaniels] (70 hemangiomas, 38 hemangiosarcomas) from 8300 canine submissions between 1989 and 2004. Signalment, location, pigmentation, size, duration, diagnosis, margins, ancillary therapy, and geographic location were recorded. Follow-up information was available for 49 cases. Each case was matched with two unaffected controls and compared using logistic regression analysis. Average age upon presentation was 8.6 years; there was no sex predilection. Risk of conjunctival tumors was statistically different among breed groups (P = 0.0010), demonstrating a propensity to occur in groups likely to have increased outdoor activity. Primary involvement occurred within nonpigmented epithelium along the leading edge of the nictitating membrane (41/108) and temporal bulbar conjunctiva (33/108). The etiology remains unknown; however, the strong site predilection, involvement of nonpigmented epithelium, and development within specific breed classes strongly suggest ultraviolet (UV) light as a significant risk factor. In a full-logistic model including breed, gender, age, and UV exposure, UV was not a statistically significant variable (P = 0.1215). In a reduced-model including UV only, significance was approached (P = 0.0696) and posthoc contrast demonstrated a significant linear trend with increasing UV exposure (P = 0.0147). In separate analysis of risks associated with hemangiosarcoma, compared with hemangioma, breed was not significant while increasing UV exposure was significant (P = 0.0381). Early surgical therapy is recommended and may be curative; however, recurrence is possible and more likely with hemangiosarcomas (11/20)."

Breed, gender and neutering status of British dogs with anal sac gland carcinoma. G. A. Polton, V. Mowat, H. C. Lee, K. A. Mckee, T. J. Scase. Vet & Comp Oncology; Sept 2006;4(3):125-131. Quote: "This study details the breed, gender and neutering status of a large cohort of British canine patients suffering from histologically confirmed anal sac gland carcinoma. Estimates of the relative risk for the development of this disease attributable to these factors are calculated. To reduce the impact of sampling errors, cases were selected from veterinary histopathology laboratories rather than referral hospital databases, and multiple estimates of the general British canine population were used. The weaknesses of the statistical assumptions made are discussed. There was no evidence to support a gender predisposition for the development of this condition. English cocker spaniels are significantly over-represented, with a mean relative risk estimate of 7.3. The mean relative risk estimate associated with being neutered was 1.4; the effect of neutering appeared to be more significant in male dogs compared with that in female dogs."

New aspects of canine pyometra. R. Hagman, Doctoral thesis, Swedish University of Agricultural Sciences, Uppsala, 2004. Quote: "Breeds with high risk of the development of pyometra in the present study were Collie (rough-haired), Rottweiler, Cavalier King Charles Spaniel, Bernese Mountain Dog and Golden Retriever. ... The interactions with biological age could be interpreted as that in some breeds (e.g. Rottweiler, rough-haired Collie, Golden Retriever, and Cavalier King Charles Spaniel), the risk of pyometra actually increases more and at an earlier age compared with other breeds. These breeds may carry a higher genetic predisposition for pyometra than other breeds."

Corneal squamous cell carcinoma in dogs with a history of chronic keratitis. R. R. Dubielzig, C. S. Schobert and J. Dreyfus. Vet Ophth; 2008;11(6):413–429 (Abstract 101). Quote: "Purpose: Corneal squamous cell carcinoma (SCC) is a rare tumor in dogs. The COPLOW has seen a recent increase in primary SCC in the axial cornea. We report here on 25 cases. Methods: Twenty-five cases of primary axial corneal SCC were selected from the COPLOW collection which includes more that 6000 neoplastic specimens. ... Results: The number of canine corneal SCC has risen in the past several years from 1 case per year from 1998 to 2004, jumping to 6 cases in 2005, 8 cases in 2006, and 7 cases in 2007. Brachycephalic breeds are overrepresented. The breed distribution included 8 Pugs, 5 Bulldog, 2 Boxers, 2 Greyhound, 2 Shi Tzu, 2 Border Collie, 2 Pekinese, 1 Bassett, 1 Chow, 1 Cocker, and 1 Cavalier King Charles Spaniel. No correlation to sex was found. Out of the 25 cases, 21 showed signs of chronic keratitis prior to developing SCC. In the remaining 4 cases the prior corneal history was unknown. Within the group of 25, 10 cases had been treated with cyclosporine alone, 4 with tacrolimus alone, 5 with both cyclosporine and tacrolimus, and 6 treated with other drugs or unknown. Follow-up information was obtained from 23 cases with a follow-up interval of between 5 days and 31 months (mean: 7.9 months). Three dogs had died for reasons unrelated to the ocular disease. One dog had recurrent disease extending deeply into the cornea. Conclusions: Brachycephalic dogs with a background of chronic keratitis that are treated with nonsteroidal antiinflammatory drugs are at risk to develop axial corneal SCC. The increase in annual cases of SCC suggests that this phenomenon is a developing problem."

Examining the heritability of anal sac gland carcinoma in cocker spaniels. Gerry Polton. J Sm Animal Prac; Jan 2009;50(1):57. Quote: "English cocker spaniels, and to a lesser extent springer and cavalier King Charles spaniels, are at higher risk of developing anal sac gland tumours than other dogs. ... If colleagues have encountered this tumour in an English cocker spaniel, a springer spaniel or a cavalier King Charles spaniel, it would be of great value to this project if a blood sample and/or the affected patient’s pedigree certificate could be submitted for inclusion in the analyses. ... For further information or to submit blood or pedigrees please contact Gerry Polton at North Downs Specialist Referrals, Friesian Building 3&4, Brewerstreet Dairy Business Park, Brewer Street, Bletchingley, Surrey RH1 4QP, UK. Tel: +44 (0) 1883 741440, Fax: +44 (0) 1883 347030. E-mail: gerrypolton@gmail.com website: www.ndsr.co.uk"

Association between anal sac gland carcinoma and dog leukocyte antigen-DQB1 in the English Cocker Spaniel. J Aguirre-Hernández; G Polton; L J Kennedy; D R Sargan. Tissue antigens 2010;76(6):476-81. Quote: "Anal sac gland carcinomas occur frequently in English Cocker Spaniels and, to a lesser extent, in other spaniel breeds. The disease typically presents in dogs aged 8 years or older and frequently metastasises to the local lymph nodes. The association between anal sac gland carcinoma in English Cocker Spaniels and the major histocompatibility complex class II loci (the dog leukocyte antigen loci DLA-DRB1, -DQA1, -DQB1) was investigated in 42 cases and 75 controls. Based on a corrected error rate of 0.017 for each test, the allele distribution in DLA-DRB1 showed no significant difference between cases and controls (P value = 0.019), while a significant difference was obtained for DLA-DQA1 and -DQB1 alleles (P values are 0.010 and 3.3 × 10⁻⁵). The DLA-DQB1*00701 allele was the most common in both cases and controls, but it had a higher frequency among the former (0.89) than in the latter (0.61), while the second most common allele had a higher frequency in the controls (0.23) than in the cases (0.07). Haplotype distributions were also significantly different between the two groups (P value = 1.61 × 10⁻⁴). This is the second disease in English Cocker Spaniels for which the most common DLA-DQB1 allele in the breed has been shown to have a higher frequency in cases than controls, while the second most common allele in the breed (*02001) has a significantly higher frequency in the controls, compared with the cases."

The development of multiple cutaneous inverted papilloma following ovariohysterectomy in a dog. Munday, J.S.; French, A.F.; MacNamara, A.R. N.Zeal. Vet. J.; June 2010;58(3):168-171(4). Quote: "Case History: Ovariohysterectomy was performed on an adult Cavalier King Charles Spaniel. The skin that had been clipped for surgery was noticed to be erythematous 8 days later. Clinical and Pathological Findings: Poorly defined patches containing multiple papules were visible bilaterally within the clipped skin. These became larger over the following 2 weeks, and samples were collected for histology. Seven days later, the lesions were multiple raised masses, up to 5 cm in diameter. Histology revealed numerous cup-shaped epidermal proliferations extending into the dermis. The presence of keratin ocytes with increased quantities of blue-grey cytoplasm, and koilocytosis suggested papillomaviral infection; Canis familiaris papillomavirus (CfPV-2) DNA was amplified from two separate samples. Complete regression was observed 8 weeks after the lesions had been initially observed. Diagnosis: Multiple inverted papilloma confined to skin that had been clipped for surgery. Clinical Relevance: This is the first time that the development of canine cutaneous papillomas has been associated with surgery. The nature of the association between surgery and development of the papillomas is uncertain. However, it is possible that damage to superficial skin could promote the formation of papillomas. This is the first identification of CfPV-2 in New Zealand."

Unilateral facial myokymia in a dog with an intracranial meningioma. Holland, CT; Holland, JT; Rozmanec, M. Austr Vet J; Sept 2010;88(9):357-361(5). Quote: "A 23-month-old castrated male Cavalier King Charles spaniel was evaluated because of a 6-month history of unusual rippling/undulating movements of the right facial muscles that were continuous and persisted during sleep. Neurological examination revealed narrowing of the right palpebral fissure and unilateral right-sided facial myokymia that was characterised by myokymic, and to a lesser degree, neuromyotonic discharges on concentric needle electromyographic examination. After persisting unchanged for almost 2.5 years from its onset, the facial myokymia gradually disappeared over a 6-month period concomitant with the emergence of a persistent ipsilateral facial paralysis and head tilt. At 5 years and 9 months after the first examination, signs of ipsilateral lacrimal, pharyngeal and laryngeal dysfunction became evident and the dog was euthanased. Postmortem examination identified a malignant (WHO grade III) meningioma in the right cerebellopontomedullary angle that compressed the ventrolateral cranial medulla, effaced the jugular foramen and internal acoustic meatus and extended into the facial canal of the petrous temporal bone. Novel findings were the unique observation of isolated unilateral facial myokymia preceding diagnosis of a meningioma affecting facial nerve function within the caudal cranial fossa and the remarkably long duration of neurological signs (75 months) attributable to the neoplasm."

Discovery and Canine Preclinical Assessment of a Nontoxic Procaspase-3–Activating Compound. Quinn P. Peterson, Danny C. Hsu, Chris J. Novotny, Diana C. West, Dewey Kim, Joanna M. Schmit, Levent Dirikolu, Paul J. Hergenrother, Timothy M. Fan. J.CancerRes. Sept. 2010;70:7232-7241. Quote: "A critical event in the apoptotic cascade is the proteolytic activation of procaspases to active caspases. The caspase autoactivating compound PAC-1 induces cancer cell apoptosis and exhibits antitumor activity in murine xenograft models when administered orally as a lipid-based formulation or implanted s.c. as a cholesterol pellet. However, high doses of PAC-1 were found to induce neurotoxicity, prompting us to design and assess a novel PAC-1 derivative called S-PAC-1. Similar to PAC-1, S-PAC-1 activated procaspase-3 and induced cancer cell apoptosis. However, S-PAC-1 did not induce neurotoxicity in mice or dogs. Continuous i.v. infusion of S-PAC-1 in dogs led to a steady-state plasma concentration of ∼10 μmol/L for 24 to 72 hours. In a small efficacy trial of S-PAC-1, evaluation of six pet dogs with lymphoma revealed that S-PAC-1 was well tolerated and that the treatments induced partial tumor regression or stable disease in four of six subjects. Our results support this canine setting for further evaluation of small-molecule procaspase-3 activators, including S-PAC-1, a compound that is an excellent candidate for further clinical evaluation as a novel cancer chemotherapeutic."

Superficial corneal squamous cell carcinoma occurring in dogs with chronic keratitis. Jennifer Dreyfus, Charles S. Schobert, Richard R. Dubielzig. Vet Ophth; May 2011;14(3):161-168. Quote: "Objective: Canine corneal squamous cell carcinoma (SCC) is a rare tumor, with only eight cases previously published in the veterinary literature. The Comparative Ocular Pathology Lab of Wisconsin (COPLOW) has diagnosed 26 spontaneously occurring cases, 23 in the past 4 years [three of which were cavalier King Charles spaniels]. This retrospective study describes age and breed prevalence, concurrent therapy, biologic behavior, tumor size and character, and 6-month survival rates after diagnosis. Results: A search of the COPLOW database identified 26 corneal SCC cases diagnosed from 1978 to 2008. There is a strong breed predilection (77%) in brachycephalic breeds, particularly those prone to keratoconjunctivitis sicca. The mean age was 9.6 years (range 6–14.5 years). Follow-up information >6 months was available for 15 of 26 cases. Recurrence occurred in the same eye in nine cases, seven of which were incompletely excised at the time of first keratectomy. No cases were known to have tumor growth in the contralateral eye and no cases of distant metastases are known. Where drug history is known, 16 of 21 dogs had a history of treatment with topical immunosuppressive therapy (cyclosporine or tacrolimus) at the time of diagnosis. Conclusion: Chronic inflammatory conditions of the cornea and topical immunosuppressive therapy may be risk factors for developing primary corneal SCC in dogs. SCC should be considered in any differential diagnosis of corneal proliferative lesions. Superficial keratectomy with complete excision is recommended, and the metastatic potential appears to be low."

Canine tonsillar squamous cell carcinoma - a multi-centre retrospective review of 44 clinical cases. A Mas, L Blackwood, P Cripps, S Murphy, J De Vos, N Dervisis, M Martano, G A Polton. J Small Anim Pract. 2011 Jul ;52 (7):359-364. Quote: " Objectives: To review the presenting clinical signs, treatment and survival of dogs with tonsillar squamous cell carcinoma and, if possible, to identify useful prognostic indicators. Methods: Medical records of 44 dogs were reviewed retrospectively. ... The breeds included: ... cavalier King Charles spaniel (four) ... Clinical signs, clinical stage, time of diagnosis, treatment and outcome were recorded. Data were analysed using the Kaplan-Meier, log-rank, Student's t test, Kruskal-Wallis test and Chi-square/Fisher Exact test as appropriate. Results: The most frequent clinical signs were cough (12 dogs, 27%), enlarged lymph nodes (11 dogs, 25%) and dysphagia (11 dogs, 25%). Anorexia and lethargy were less common but were significantly associated with a poor outcome. No matter what treatment modalities were used, survival times were short and median survival time for all the dogs in the study was 179 days. However, there were a small number of long-term survivors. Clinical Significance: Dogs with tonsillar squamous cell carcinoma that suffered anorexia and lethargy had shorter survival times than patients without these clinical signs. Although surgery, chemotherapy and radiotherapy seem to increase the median survival time of dogs diagnosed with tonsillar squamous cell carcinoma, there is no highly effective treatment for canine tonsillar squamous cell carcinoma."

Dog models of naturally occurring cancer. Jennie L. Rowell, Donna O. McCarthy, Carlos E. Alvarez. Trends in Molecular Med. July 2011;17(7):380-388. Quote: "Studies using dogs provide an ideal solution to the gap in animal models for natural disease and translational medicine. This is evidenced by approximately 400 inherited disorders being characterized in domesticated dogs, most of which are relevant to humans. There are several hundred isolated populations of dogs (breeds) and each has a vastly reduced genetic variation compared with humans; this simplifies disease mapping and pharmacogenomics. Dogs age five- to eight-fold faster than do humans, share environments with their owners, are usually kept until old age and receive a high level of health care. Farseeing investigators recognized this potential and, over the past decade, have developed the necessary tools and infrastructure to utilize this powerful model of human disease, including the sequencing of the dog genome in 2005. Here, we review the nascent convergence of genetic and translational canine models of spontaneous disease, focusing on cancer."

Pharmacokinetics and derivation of an anticancer dosing regimen for PAC-1 in healthy dogs. Pamela W. Lucas, Joanna M. Schmit, Quinn P. Peterson, Diana C. West, Danny C. Hsu, Chris J. Novotny, Levent Dirikolu, Daniel R. Deorge, Laura D. Garrett, Paul J. Hergenrother, and Timothy M. Fan. Invest New Drugs. 2011 October; 29(5): 901–911. Quote: "PAC-1 [procaspase-3 activating compound 1]  is a preferential small molecule activator of procaspase-3 and has potential to become a novel and effective anticancer agent. The rational development of PAC-1 for translational oncologic applications would be advanced by coupling relevant in vitro cytotoxicity studies with pharmacokinetic investigations conducted in large mammalian models possessing similar metabolism and physiology as people. In the present study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 hours that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 hours in duration. Using study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 hours that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 hours in duration. Using the dog as a large mammalian model, PAC-1 can be safely administered as an intravenous CRI while achieving predicted in vitro cytotoxic concentrations."

Malocclusion associated with macroglossia in a dog. Gerhard Putter. Comp. Anim. Nov/Dec 2011;16(9):12-19. Quote: "Macroglossia (defined as enlargement of the tongue but not indicating the cause) is a rare condition in dogs. The association with malocclusion has not been described before. It has been reported that resection of as much as 60% of the body of the tongue is well tolerated by dogs. Although the tongue is a very vascular organ, intraoperative haemorrhage during tongue amputation can be effectively controlled by a tourniquet at the base of the tongue. Healing of the amputation wound is usually rapid and uneventful. ... A five year old, 12 kg neutered male Cavalier King Charles Spaniel was presented with a complaint of an excessively long tongue."

Identification of genetic variation in 11 candidate genes of canine mammary tumour. K. S. Borge, A. L. Børresen-Dale, F. Lingaas. Vet. & Comp. Oncology; Dec 2011;9(4):241-250. Quote: "The incidence of canine mammary tumours (CMTs) differs significantly between breeds [cavalier King Charles spaniels are identified as being at low-risk for CMT], strongly supporting an influence of genetic risk factors. We aimed at identifying germline genetic variations in mammary tumour-associated genes in dogs and survey whether these might alter the encoded proteins. We sequenced 11 genes (BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EGFR, ESR1, HER2, PTEN, STK11 and TP53) and screened for genetic variations. Sixty-four single nucleotide polymorphisms (SNPs) were identified. Nine of the coding SNPs were non-synonymous, of which four were located in gene regions conserved across four species. Three of the non-synonymous SNPs might be damaging according to PolyPhen predictions. One of the indels identified has previously been associated with CMTs. Because of the founder effects, genetic drift and inbreeding in many dog breeds the allele frequencies of the genes studied are likely to vary significantly between breeds and contribute to the considerable difference in genetic risk associated with cancer."

Thymidine kinase assay in canine lymphoma. J. W. Elliott, P. Cripps, L. Blackwood. Vet. & Comp. Oncology; Dec 2011. Quote: "The aim of the study was to evaluate if thymidine kinase (TK) correlated with duration of first remission (DFR) or survival in dogs with lymphoma and if initial TK levels correlated with stage and substage; and also to assess if TK level at diagnosis correlated with immunophenotype. TK was assayed in 73 dogs with treatment naïve lymphoma, then again after treatment; 47% had an initial TK above the reference interval. Dogs with B-cell lymphoma had higher initial TK activities than dogs with T-cell lymphoma. TK levels were not higher in dogs with higher stage disease and TK activity prior to treatment was not associated with DFR or survival. Where TK was elevated at diagnosis, it fell into the reference range during remission. TK was normal in 53% dogs at diagnosis, which is higher than previously reported. Further studies are warranted to assess the utility of TK in dogs with lymphoma."

Parallel Synthesis and Biological Evaluation of 837 Analogues of Procaspase-Activating Compound 1 (PAC-1). Danny C. Hsu, Howard S. Roth, Diana C. West, Rachel C. Botham, Chris J. Novotny, Steven C. Schmid, Paul J. Hergenrother. ACS Comb Sci. 2012 January; 14(1):44–50. Quote: "Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of PAC-1, called S-PAC-1, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on PAC-1 was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 PAC-1 analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than PAC-1 and S-PAC-1. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3.

Lawn Pesticide WarningHousehold chemical exposures and the risk of canine malignant lymphoma, a model for human non-Hodgkin’s lymphoma. Biki B. Takashima-Uebelhoer, Lisa G. Barber, Sofija E. Zagarins, Elizabeth Procter-Gray, Audra L. Gollenberg, Antony S. Moore, Elizabeth R. Bertone-Johnson. Environmental Research. Jan 2012.; 112:171-176.  Quote: "Background: Epidemiologic studies of companion animals offer an important opportunity to identify risk factors for cancers in animals and humans. Canine malignant lymphoma (CML) has been established as a model for non-Hodgkin’s lymphoma (NHL). Previous studies have suggested that exposure to environmental chemicals may relate to development of CML. Methods: We assessed the relation of exposure to flea and tick control products and lawn-care products and risk of CML in a case–control study of dogs presented to a tertiary-care veterinary hospital (2000–2006). Cases were 263 dogs with biopsy-confirmed CML. Controls included 240 dogs with benign tumors and 230 dogs undergoing surgeries unrelated to cancer. Dog owners completed a 10-page questionnaire measuring demographic, environmental, and medical factors. Results: After adjustment for age, weight, and other factors, use of specific lawn care products was associated with greater risk of CML. Specifically, the use of professionally applied pesticides was associated with a significant 70% higher risk of CML (odds ratio(OR)=1.7; 95% confidence interval (CI)=1.1–2.7). Risk was also higher in those reporting use of self-applied insect growth regulators (OR=2.7; 95% CI=1.1–6.8). The use of flea and tick control products was unrelated to risk of CML. Conclusions: Results suggest that use of some lawn care chemicals may increase the risk of CML. Additional analyses are needed to evaluate whether specific chemicals in these products may be related to risk of CML, and perhaps to human NHL as well."

The effect of neutering on the risk of mammary tumours in dogs – a systematic review. W. Beauvais, J. M. Cardwell and D. C. Brodbelt. J.Sm.Anim.Pract, June 2012; 53(6): 314-322. Quote: "A commonly-stated advantage of neutering bitches is a significant reduction in the risk of mammary tumours, however the evidence for this has not previously been assessed by systematic review. The objectives of this study were to estimate the magnitude and strength of evidence for any effect of neutering, or age of neutering, on the risk of mammary tumours in bitches. A systematic review was conducted based on Cochrane guidelines. Peer-reviewed analytic journal articles in English were eligible and were assessed for risk of bias by two reviewers independently. Of 11,149 search results, 13 reports in English-language peer-reviewed journals addressed the association between neutering/ age at neutering and mammary tumours. Nine were judged to have a high risk of bias. The remaining four were classified as having a moderate risk of bias. One study found an association between neutering and a reduced risk of mammary tumours. Two studies found no evidence of an association. One reported “some protective effect” of neutering on the risk of mammary tumours, but no numbers were presented. Due to the limited evidence available and the risk of bias in the published results, the evidence that neutering reduces the risk of mammary neoplasia, and the evidence that age at neutering has an effect, are judged to be weak and are not a sound basis for firm recommendations."

The dog as a possible animal model for human non-Hodgkin lymphoma: a review. Laura Marconato, Maria Elena Gelain, Stefano Comazzi. Hematological Oncology. 2012.  Quote: "Lymphoma represents the most frequent hematopoietic cancer in dogs, and it shows significant overlap with the human disease. ... Diffuse large B-cell lymphoma ... DLBCL is prevalent in Cavalier King Charles Spaniel and Bassethound ... Several environmental factors have been associated with canine lymphoma, suggesting that they may contribute to lymphomagenesis. Canine lymphoma often presents in advanced stage (III–V) at diagnosis and, most commonly, has an aggressive clinical course requiring prompt treatment, which relies on the use of polychemotherapy. In this review, we will summarize the state-of-the-art of canine lymphoma epidemiology, pathobiology, diagnostic work-up and therapy, and will highlight the links to the corresponding human disease, providing evidence for the use of dog as an animal model of spontaneous disease."

Squamous papilloma in an older Cavalier King Charles. Sing Kong Yuen. Aug. 2012. SinPets.com

Rectal lymphoma in 11 dogs – a retrospective study. N. Van den Steen, D. Berlato, G. Polton, J. Dobson, J. Stewart, G. Maglennon, A. M. Hayes and S. Murphy. J.Sm.Anim.Prac. Aug 2012. Quote: "Objectives: To retrospectively evaluate the clinical behaviour and immunophenotype of lymphoma of the rectum in dogs. Methods: Eleven dogs [including a cavalier King Charles spaniel] diagnosed with lymphoma of the rectum on histopathology were retrospectively reviewed. Immunohistochemistry with CD3 and CD79a antibodies was performed at diagnosis or retrospectively. Results: Treatment protocol varied with six dogs undergoing surgery and adjuvant chemotherapy, two received chemotherapy after only incisional biopsy, one had surgical resection only, one was treated symptomatically and one dog was not treated. Chemotherapy treatment consisted of either a -low-dose COP (cyclophosphamide - prednisolone - vincristine) protocol (four dogs) or a six-week CHOP-based (cyclophosphamide - vincristine - -prednisolone - anthracycline) protocol (four dogs). Dogs that received chemotherapy lived significantly longer than dogs that did not receive chemotherapy (2352 versus 70 days). Median survival time was not reached, and there was an overall mean survival time of 1697 days. Immuno-histochemistry was performed in 10 of 11 samples, and was consistent with B-cell -lymphoma in all cases. Clinical Significance: Canine lymphoma of the rectum is associated with a favourable prognosis. Immunohistochemical evaluation of these lesions was consistent with B-cell lymphoma in all cases in which it was examined."

Single Agent Polysaccharopeptide Delays Metastases and Improves Survival in Naturally Occurring Hemangiosarcoma. Dorothy Cimino Brown and Jennifer Reetz. Evidence-Based Complementary and Alternative Medicine 2012; Article ID Coriolus versicolor mushroom384301. Quote: "The 2008 World Health Organization World Cancer Report describes global cancer incidence soaring with many patients living in countries that lack resources for cancer control. Alternative treatment strategies that can reduce the global disease burden at manageable costs must be developed. Polysaccharopeptide (PSP) is the bioactive agent from the mushroom Coriolus versicolor (right). Studies indicate PSP has in vitro antitumor activities and inhibits the growth of induced tumors in animal models. Clear evidence of clinically relevant benefits of PSP in cancer patients, however, is lacking. The investment of resources required to complete large-scale, randomized controlled trials of PSP in cancer patients is more easily justified if antitumor and survival benefits are documented in a complex animal model of a naturally occurring cancer that parallels human disease. Because of its high metastatic rate and vascular origin, canine hemangiosarcoma is used for investigations in antimetastatic and antiangiogenic therapies. In this double-blind randomized multidose pilot study, high-dose PSP significantly delayed the progression of metastases and afforded the longest survival times reported in canine hemangiosarcoma. These data suggest that, for those cancer patients for whom advanced treatments are not accessible, PSP as a single agent might offer significant improvements in morbidity and mortality."

Breed Variations in the Incidence of Pyometra and Mammary Tumours in Swedish Dogs. S. Jitpean, R. Hagman, B. Ström Holst, O.V. Höglund, A. Pettersson, A. Egenvall. Reproduction in Domestic Animals. Dec. 2012. Quote: "Dogs enrolled in a Swedish insurance company (during 1995–2006) were studied for development of pyometra and mammary tumours (MTs), with special attention to breed and age. There were over 260 000 female dogs with over 1 000 000 dog-years at risk (DYAR) in the database, using data on bitches up to 10 years of age and 110 breeds with over 1000 DYAR. In total, 20 423 bitches were diagnosed with pyometra and 11 758 with MTs and 30 131 with either or both of the two diseases. [48% of female cavalier King Charles spaniels developed pyometra, and 15% of them developed mammary tumors, and 54% of them developed either or both pyometra and mammary tumors, by the age of ten years.] The incidence rate (IR) for pyometra was 199 (95% CI 196–202), for MTs 112 (95% CI 110–114) and for either or both of the two diseases 297 (95% CI 294–301) dogs per 10 000 DYAR. The mean age of diagnosis pyometra was 7.0 years (SD ± 2.2), MTs 8.0 years (SD ± 1.6). In all breeds, the overall proportion of the bitches that developed disease by 10 years of age was for pyometra 19%, MTs 13%, and either or both of two diseases 30%. The top 10 breeds diagnosed with either or both of the two diseases were the Leonberger (73%), Irish Wolfhound (69%), Bernese Mountain Dog (69%), Great Dane (68%), Staffordshire Bull Terrier (66%), Rottweiler (65%), Bullterrier (62%), Doberman (62%), Bouvier des Flandres (60%), Airdaleterrier (60%). These data provide information of the combined disease incidence in a large number of different breeds. Breed variations in incidence rate suggests genetic components in disease development. Our study may be valuable in the search for genetic risk-factors or protective factors."

Evaluation of an anal sac adenocarcinoma tumor in a Spitz dog. Javad Javanbakht, Abbas Tavassoli, Atefeh Sabbagh, Mehdy Aghamohammmad Hassan, Shohreh Alian Samakkhah, Radmehr Shafiee, Ali Lakzian, Vahideh Rahmani Ghalee, and Sonia Shoja Gharebagh. Asian Pac J Tropical Biomed. Jan. 2013; 3(1):74-78. Quote: "Anal Gland Adenocarcinoma is a cancer of the apocrine gland, located inside of the anal sac. Canine anal glands are scent glands that produce an oily secretion. They are found on either side of the dog's anus between the internal and external sphincter. These tumors tend to be locally invasive and can metastasize early. However, this cancer is associated with a prolonged clinical course. Breeds more commonly affected include English Cocker Spaniels, Cavalier King Charles Spaniels, German Shepherds and English Springer Spaniels. Both genders of dogs are equally affected. The cause of this tumor is unknown."

Breed-Predispositions to Cancer in Pedigree Dogs. Jane M. Dobson. ISRN Vet.Sci. 2013. Quote: "Cancer is a common problem in dogs and although all breeds of dog and crossbred dogs may be affected, it is notable that some breeds of pedigree dogs appear to be at increased risk of certain types of cancer suggesting underlying genetic predisposition to cancer susceptibility. Although the aetiology of most cancers is likely to be multifactorial, the limited genetic diversity seen in purebred dogs facilitates genetic linkage or association studies on relatively small populations as compared to humans, and by using newly developed resources, genome-wide association studies in dog breeds are proving to be a powerful tool for unravelling complex disorders. This paper will review the literature on canine breed susceptibility to histiocytic sarcoma, osteosarcoma, haemangiosarcoma, mast cell tumours, lymphoma, melanoma, and mammary tumours including the recent advances in knowledge through molecular genetic, cytogenetic, and genome wide association studies. ... In our clinic (Cambridge, UK) ... cavalier King Charles spaniels ... are under-represented [for mast cell tumors]. ... Canine anal sac gland carcinoma (ASGC) is a relatively uncommon malignancy arising from the apocrine glands in the walls of the anal sacs. This tumour is invasive and metastatic in nature and is often associated with a paraneoplastic hypercalcaemia. Although ASGC [anal sac gland carcinoma] may arise in any breed of dog the English cocker spaniel and to a lesser degree other spaniel types (English springer and cavalier King Charles) have been reported to be predisposed to development of this tumour."

Neutering Dogs: Effects on Joint Disorders and Cancers in Golden Retrievers. Gretel Torres de la Riva, Benjamin L. Hart, Thomas B. Farver, Anita M. Oberbauer, Locksley L. McV Messam, Neil Willits, Lynette A. Hart. PLOSone. Feb. 2013.   Excerpt: "Hemangiosarcoma is a cancer that is affected by neutering in females. A study of cardiac tumors in dogs found that cardiac HSA for spayed females was greater than 4 times that of intact females. A study on splenic HSA found the spayed females had more than 2 times the risk of developing this tumor as intact females. Neither of these studies separated early- versus late-spayed females with regard to increased risk, and neither focused on just one breed. A study on the epidemiology of LSA (lymphoma) in dogs, for comparison with human lymphoma, found that intact females had a significantly lower risk of developing this cancer than neutered females or neutered males or intact males. Another cancer of concern is prostate cancer, which occurs in neutered males about four times as frequently as in intact males. A study on cutaneous mast cell tumors (MCT) in several dog breeds, including the Golden Retriever, examined risk factors such as breed, size, and neuter status. Although early versus late neutering was not considered, the results showed a significant increase in frequency of MCT in neutered females; four times greater than that of intact females. In contrast to the rather strong evidence for neutering males and/or females as a risk factor for OSA, HSA, LSA, MCT, and prostate cancer, evidence for neutering as protection against a dog acquiring one or more cancers is weak. The most frequently mentioned is mammary cancer (MC). However, a recent systematic review of published work on neutering and mammary tumors found the evidence that neutering reduces the risk of mammary neoplasia to be weak, at best."

Breed predispositions in canine mast cell tumour: A single centre experience in the United Kingdom. James Warland, Jane Dobson. Vet.J. April 2013. Quote: "Genetic factors play a major role in carcinogenesis. Many breeds have been reported to be predisposed to mast cell tumour (MCT) development using various methods and diverse control populations. A database of 222 dogs with MCT seen at a UK university referral hospital was compared to three control populations, namely, an insured population of UK dogs, registrations with the UK Kennel Club and other dogs seen through the same hospital. Odds ratios were calculated for each breed. Boxers, Labradors, Golden Retrievers and Staffordshire Bull Terriers appeared predisposed to MCT development. English Springer Spaniels, English Cocker Spaniels, German Shepherd Dogs, West Highland White Terriers and Cavalier King Charles Spaniels were underrepresented."

Canine Melanoma Vaccine. Heather Wilson-Robles. Clinicians Brief. August 2013:15-16. Quote: "Malignant melanoma is the most common malignant oral tumor in dogs, but it can also occur in other locations (eg, nail bed, eye, perineum, nasal cavity, GI tract, skin). ... Oncept (Merial, petcancervaccine.com), immunotherapy labeled for dogs with stage II or III oral melanoma, can help achieve local disease control.4 This therapy uses an orthologous DNA (different species) vaccine against tyrosinase, a melanosomal glycoprotein needed for melanin synthesis, to induce an antityrosinase immune response.5 Tyrosinase has been overexpressed in melanomas of various species.6-8 Although the human tyrosinase protein differs enough from the canine tyrosinase protein to allow human tyrosinase protein stimulation of an immune response in canine patients, in some cases the human tyrosinase protein is similar enough to the canine tyrosinase protein that the immune response is effective against canine melanoma cells."

Successful transendoscopic oesophageal mass ablation in two dogs with Spirocerca lupi associated oesophageal sarcoma. E. Yas, G. Kelmer, A. Shipov, J. Ben-Oz and G. Segev. J.Sm.Anim.Pract. Sept. 2013;54(9):495-498. Quote: "This report describes two cases of oesophageal tumours managed by transendoscopic neodymium:yttrium-aluminum-garnet laser ablation and polypectomy snare electrocautery. ... [including] A 4-year-old, neutered male, Cavalier King Charles spaniel ... In each dog oesophagoscopy revealed caudal oesophageal masses, suspected to be Spirocerca lupi-induced oesophageal neoplasia. To resect the masses, transendoscopic neodymium:yttrium-aluminum-garnet laser ablation was used in the first case and polypectomy snare electrocautery in the second. Recovery was uneventful. Histopathology was consistent with oesophageal fibrosarcoma and osteosarcoma in each case, respectively. Follow-up oesophagoscopy revealed apparently healthy oesophageal tissue except for focal scar tissue in the first case. Transendoscopic laser ablation and polypectomy snare electrocautery is a potential non-invasive, cost effective alternative for surgical oesophageal mass resection."

Extranodal lymphoma with peripheral nervous system involvement in a dog. Ueno H, Miyoshi K, Fukui S, Kondo Y, Matsuda K, Uchide T. J.Vet.Med.Sci Jan. 2014. Quote: "An 8-year-old neutered female Cavalier King Charles Spaniel was evaluated for progressing right forelimb lameness. Upon magnetic resonance imaging, the right-sided radius nerves and the caudal brachial plexus were swelled. The histological and molecular biological diagnosis of partial the C8 spinal nerve was T-cell lymphoma. Co-administration of lomustine and irradiation was started. However, this therapy was ineffective. At necropsy, neoplastic tissues were seen extending into the subarachnoid space of the spinal cord, the liver, pancreas and kidneys as gross findings. A large mass was also identified occupying the caudal thorax. Histologic findings included infiltration in these organs and mass by neoplastic lymphocytes. To date, involvement of peripheral nerves (neurolymphomatosis) is rarely reported in veterinary species."

Evaluation of the risk and age of onset of cancer and behavioral disorders in gonadectomized Vizslas. M. Christine Zink, Parvene Farhoody, Samra E. Elser, Lynda D. Ruffini, Tom A. Gibbons, Randall H. Rieger. JAVMA Feb. 2014;244(3):309-319. Quote: "Objective: To investigate associations between age at gonadectomy and estimated risk or age at diagnosis of neoplastic and behavioral disorders in Vizslas. Design: Retrospective cohort study. Animals: 2,505 Vizslas born between 1992 and 2008. Procedures: Data on demographics, gonadectomy status, and age at diagnosis of disease or disorder were obtained with an anonymous online survey and analyzed. Results: Dogs gonadectomized at ≤ 6 months, between 7 and 12 months, or at > 12 months of age had significantly increased odds of developing mast cell cancer, lymphoma, all other cancers, all cancers combined, and fear of storms, compared with the odds for sexually intact dogs. Females gonadectomized at ≤ 12 months of age and males and females gonadectomized at > 12 months of age had significantly increased odds of developing hemangiosarcoma, compared with the odds for sexually intact dogs. Dogs gonadectomized at ≤ 6 months of age had significantly increased odds of developing a behavioral disorder. The younger the age at gonadectomy, the earlier the mean age at diagnosis of mast cell cancer, cancers other than mast cell, hemangiosarcoma, lymphoma, all cancers combined, a behavioral disorder, or fear of storms. (Mast cell cancer: 3.5 times higher incidence in neutered male and female dogs, independent of age at the time of neutering. Hemangiosarcoma: 9.0 times higher incidence in neutered females compared to nonneutered females, independent of age at the time spaying was performed. No difference in incidence of this disease was found for neutered versus nonneutered males. Lymphoma (lymphosarcoma): 4.3 times higher incidence in neutered male and female dogs, independent of age at the time of neutering. Other types of cancer: 5.0 times higher incidence in neutered male and female dogs. The younger a dog was at the time of neutering the younger the age of the dog at the time the cancer was diagnosed. All cancers combined: 6.5 times higher incidence of cancer in neutered females compared to nonneutered females; 3.6 times higher incidence of cancer in neutered males compared to nonneutered males.) Conclusions and Clinical Relevance: Additional studies are needed on the biological effects of removing gonadal hormones and on methods to render dogs infertile that do not involve gonadectomy. Veterinarians should discuss the benefits and possible adverse effects of gonadectomy with clients, giving consideration to the breed of dog, the owner's circumstances, and the anticipated use of the dog."

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